Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy

Int J Mol Sci. 2021 Apr 1;22(7):3681. doi: 10.3390/ijms22073681.


Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and 65 age and sex matched healthy controls were recruited and assigned to one of four study phases: (i) discovery for sample size determination; (ii) candidate screening; (iii) candidate validation; and (iv) verifying the performance of the validated miRNA panel in four patients treated with erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement under development for MNGIE. Quantitative PCR (qPCR) was used to profile miRNAs in serum and/or plasma samples collected for the discovery, validation and performance phases, and next generation sequencing (NGS) analysis was applied to serum samples assigned to the candidate screening phase. Forty-one differentially expressed candidate miRNAs were identified in the sera of patients (p < 0.05, log2 fold change > 1). The validation cohort revealed that of those, 27 miRNAs were upregulated in plasma and three miRNAs were upregulated in sera (p < 0.05). Through binary logistic regression analyses, five plasma miRNAs (miR-192-5p, miR-193a-5p, miR-194-5p, miR-215-5p and miR-34a-5p) and three serum miRNAs (miR-192-5p, miR-194-5p and miR-34a-5p) were shown to robustly distinguish MNGIE from healthy controls. Reduced longitudinal miRNA expression of miR-34a-5p was observed in all four patients treated with EE-TP and coincided with biochemical and clinical improvements. We recommend the inclusion of the plasma exploratory miRNA biomarker panel in future clinical trials of investigational therapies for MNGIE; it may have prognostic value for assessing clinical status.

Keywords: MNGIE; Mitochondrial neurogastrointestinal encephalomyopathy; biomarker; erythrocyte encapsulated thymidine phosphorylase; miR-34a-5p; miRNA; mitochondrial disease; outcome measures; thymidine phosphorylase.

Publication types

  • Validation Study

MeSH terms

  • Biomarkers / blood
  • Case-Control Studies
  • Gene Expression Profiling
  • Humans
  • Intestinal Pseudo-Obstruction / blood*
  • MicroRNAs / blood*
  • Muscular Dystrophy, Oculopharyngeal / blood*
  • Ophthalmoplegia / blood
  • Ophthalmoplegia / congenital*


  • Biomarkers
  • MicroRNAs

Supplementary concepts

  • Visceral myopathy familial external ophthalmoplegia